QSAR modeling of human serum protein binding with several modeling techniques utilizing structure-information representation

Four modeling techniques, using topological descriptors to represent molecular structure, were employed to produce models of human serum protein binding (% bound) on a data set of 1008 experimental values, carefully screened from publicly available sources. To our knowledge, this data is the largest set on human serum protein binding reported for QSAR modeling. The data was partitioned into a training set of 808 compounds and an external validation test set of 200 compounds. Partitioning was accomplished by clustering the compounds in a structure descriptor space so that random sampling of 20% of the whole data set produced an external test set that is a good representative of the training set with respect to both structure and protein binding values. The four modeling techniques include multiple linear regression ( MLR), artificial neural networks ( ANN), k-nearest neighbors ( kNN), and support vector machines (SVM). With the exception of the MLR model, the ANN, kNN, and SVM QSARs were ensemble models. Training set correlation coefficients and mean absolute error ranged from r(2)=0.90 and MAE=7.6 for ANN to r(2)=0.61 and MAE=16.2 for MLR. Prediction results from the validation set yielded correlation coefficients and mean absolute errors which ranged from r(2)=0.70 and MAE=14.1 for ANN to a low of r(2)=0.59 and MAE=18.3 for the SVM model. Structure descriptors that contribute significantly to the models are discussed and compared with those found in other published models. For the ANN model, structure descriptor trends with respect to their affects on predicted protein binding can assist the chemist in structure modification during the drug design process.